Mastocytosis van Anrooij, Bjorn
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van Anrooij, B. (2019). Mastocytosis: A disease at the crossroads of hematology and allergology. University of Groningen.
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Chapter 4
Published in: Scandinavian Journal of Immunology, 2016, 83, 465– 472
4
IDENTIFICATION OF BIOLOGICAL AND PHARMACEUTICAL MAST CELL‐ AND BASOPHIL‐RELATED TARGETS
Authors
O. Klein 1, F. Ngo‐Nyekel 2 T. Stefanache 3, R. Torres 4 , M. Salomonsson 5, J. Hallgren 6, M. Rådinger 7, M. Bambouskova, 8, S. Cohen‐Mor 9, B. Dema 10, C. G. Rose 11, M. Abrink 12, G. Ainooson 13, A. Paivandy 14 V. G. Pavlova 15, E. Serrano‐ Candelas 16, Y. Yu 17, L. Hellman 18, B. M. Jensen 19, B. Vvan Anrooij 20, J. Grootens 21, H. K. Gura 22, M. Stylianou 23, A. Tobio 24, U. Blank 2
Author contributions
All authors contributed equally to the writing of this manuscript being responsible for the following indicated topic:
(i) mast cell and basophil development (authors 1–7),
(ii) mast cell- and basophil-deficient animal models (authors 8–13), (iii) differences between mouse and human mast cells
and basophils (authors 13–20),
(iv) mast cells and basophils as targets for tyrosine kinase inhibitors (authors 21–27).
Introduction
Mast cells and basophils have been studied mainly regarding their implication in IgE-mediated allergic disease. Yet, it has become clear that apart from the high‐affinity IgE receptor (FcεRI), these cells can respond to many different inflammatory stimuli via expression of a large variety of additional receptors making them prime effectors and regulators in inflammation and immunity. Besides highlighting mast cell involvement in different acute and chronic inflammatory and autoimmune diseases, studies have also revealed their beneficial functions.
The COST Action BM1007 ‘Mast cells and Basophils – Targets for Innovative Therapies’ represented a network of researchers analysing to a large part the physiological and pathological roles of mast cells and basophils in the organism in order to come up with new treatment strategies. Within this frame, the task of one working group was to identify biological and pharmaceutical mast cell and basophil related targets through the identification of relevant pathways, the means to modulate mast cell and basophil functions, the promotion of studies in the human system as well as by the validation of pharmacological approaches and preclinical models. In February 2015, the third and last training school related to this COST action was held in Uppsala, Sweden. The school gathered 20 students together with eight trainers from 11 countries all across Europe in a relaxed study atmosphere to discuss hot mast cell topics. These topics were as follows: (i) mast cell and basophil development in vivo and in vitro, (ii) mast cell and basophil deficient mouse strains, (iii) the difference between human and mouse mast cells and basophils and (iv) Are kinase inhibitors potential targets for mast cell and basophil driven diseases? Here, we summarized the conclusion reached during this two day training school in the form of a commentary report.
4
IDENTIFICATION OF BIOLOGICAL AND PHARMACEUTICAL MAST CELL‐ AND BASOPHIL‐RELATED TARGETS
Authors
O. Klein 1, F. Ngo‐Nyekel 2 T. Stefanache 3, R. Torres 4 , M. Salomonsson 5, J. Hallgren 6, M. Rådinger 7, M. Bambouskova, 8, S. Cohen‐Mor 9, B. Dema 10, C. G. Rose 11, M. Abrink 12, G. Ainooson 13, A. Paivandy 14 V. G. Pavlova 15, E. Serrano‐ Candelas 16, Y. Yu 17, L. Hellman 18, B. M. Jensen 19, B. Vvan Anrooij 20, J. Grootens 21, H. K. Gura 22, M. Stylianou 23, A. Tobio 24, U. Blank 2
Author contributions
All authors contributed equally to the writing of this manuscript being responsible for the following indicated topic:
(i) mast cell and basophil development (authors 1–7),
(ii) mast cell- and basophil-deficient animal models (authors 8–13), (iii) differences between mouse and human mast cells
and basophils (authors 13–20),
(iv) mast cells and basophils as targets for tyrosine kinase inhibitors (authors 21–27).
Introduction
Mast cells and basophils have been studied mainly regarding their implication in IgE-mediated allergic disease. Yet, it has become clear that apart from the high‐affinity IgE receptor (FcεRI), these cells can respond to many different inflammatory stimuli via expression of a large variety of additional receptors making them prime effectors and regulators in inflammation and immunity. Besides highlighting mast cell involvement in different acute and chronic inflammatory and autoimmune diseases, studies have also revealed their beneficial functions.
The COST Action BM1007 ‘Mast cells and Basophils – Targets for Innovative Therapies’ represented a network of researchers analysing to a large part the physiological and pathological roles of mast cells and basophils in the organism in order to come up with new treatment strategies. Within this frame, the task of one working group was to identify biological and pharmaceutical mast cell and basophil related targets through the identification of relevant pathways, the means to modulate mast cell and basophil functions, the promotion of studies in the human system as well as by the validation of pharmacological approaches and preclinical models. In February 2015, the third and last training school related to this COST action was held in Uppsala, Sweden. The school gathered 20 students together with eight trainers from 11 countries all across Europe in a relaxed study atmosphere to discuss hot mast cell topics. These topics were as follows: (i) mast cell and basophil development in vivo and in vitro, (ii) mast cell and basophil deficient mouse strains, (iii) the difference between human and mouse mast cells and basophils and (iv) Are kinase inhibitors potential targets for mast cell and basophil driven diseases? Here, we summarized the conclusion reached during this two day training school in the form of a commentary report.
4
Mast cell and basophil development in vivo and in vitroIdentifying and mapping the different stages of mast cell and basophil development and differentiation is important for designing specific drugs targeting these cells. Current knowledge on the mast cell maturation and differentiation process has been reviewed recently1, indicating an important role of transcription factors and surface molecules such as integrins and cytokine receptors. New types of regulators have been identified by a screen of microRNAs (miRNAs) expressed during differentiation of mast cells from bone marrow. Very specific miRNA patterns were found to be expressed governing the expression of differentiation and maturation markers such as KIT and the high‐affinity IgE receptor (FcεRI)2. miRNAs play critical roles in maintaining gene expression at appropriate levels, and these small molecules may thus be new potential targets to inhibit particular steps of mast cell differentiation and/or maturation.
Another important aspect of characterizing mast cell and basophil development is to establish better protocols to study these cells in vitro. Due to the low numbers of basophils in blood, many experimental procedures are difficult to perform. Making researchers to rely on basophil cell lines or bone marrow derived basophils differentiated in vitro. Likewise, mast cells reach full maturation in tissues and mature mast cells are not found in the circulation1. Hence, researchers generally use established cell lines or mast cells differentiated in vitro from progenitor cells (i.e. cord blood, bone marrow). Accordingly, better understanding of mast cell and basophil development and maturation should yield better protocols for differentiating them in vitro. Currently, some contradictions arise from the literature regarding the cytokines and factors critical for mast cell and basophil differentiation. For example, while differentiation of murine bone marrow derived mast cells can be achieved with IL3 in the absence of stem cell factor (SCF), human mast cells are typically differentiated using IL6 and SCF. Manninka et al. have characterized in vitro culture conditions suitable for human mast cells and suggested that human mast cells arise from a committed progenitor distinct from other myeloid cells 3.
Since mast cells reach final maturation in tissues, it is plausible that other tissue‐resident cells supply additional maturation signals that may be responsible for the existing considerable heterogeneity.
Consistent with this notion, mast cells in various types of tissues present different phenotypes, such as connective tissue or mucosal mast cells. Hsieh et al.4 have shown that airway epithelial cells can provide necessary factors for expression of tryptase/chymase in cord blood differentiated mast cells. They also demonstrated that culture conditions affect their capacity to release leukotrienes. This finding is important since most studies tend to characterize human mast cells only by their protease content. Importantly, when attempting to study mast cells in vitro, one should consider the type of mast cell that is relevant for the physiological aspect of the study and adjust culture conditions, accordingly. Thus, to model human lung mast cells, special culture conditions may be required such as coculture with airway epithelial cells along with IL-3 and IL-4. 5
Cell differentiation is tightly regulated by transcription factors. Mast cell and basophil maturation and differentiation require GATA and STAT transcription factor families. 6,7However, new transcription factors continue to be discovered. In mice, interferon regulatory factor 8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates basophil and mast cell development 8. It is expressed in granulocyte progenitors but not in basophils, mast cells and basophil‐/mast cell‐restricted progenitors. However, in IRF8 knockouts, mast cell and basophil development is inhibited supporting a role in the generation of mast cell and basophil progenitors, likely involving its function as a transactivator of GATA2. 8 The complexity of the gene expression regulation during cell differentiation highlights the need for searching additional candidate transcription factors.
Current drugs used for mast cell and basophil induced pathologies are non-specific or target only a single mediator like antihistamines calling for more selective targets and knowledge about factors determining mast cell and basophil development. Improved in vitro systems to model the in vivo mast cell and basophil phenotypes are also crucial for the research community.
4
Mast cell and basophil development in vivo and in vitroIdentifying and mapping the different stages of mast cell and basophil development and differentiation is important for designing specific drugs targeting these cells. Current knowledge on the mast cell maturation and differentiation process has been reviewed recently1, indicating an important role of transcription factors and surface molecules such as integrins and cytokine receptors. New types of regulators have been identified by a screen of microRNAs (miRNAs) expressed during differentiation of mast cells from bone marrow. Very specific miRNA patterns were found to be expressed governing the expression of differentiation and maturation markers such as KIT and the high‐affinity IgE receptor (FcεRI)2. miRNAs play critical roles in maintaining gene expression at appropriate levels, and these small molecules may thus be new potential targets to inhibit particular steps of mast cell differentiation and/or maturation.
Another important aspect of characterizing mast cell and basophil development is to establish better protocols to study these cells in vitro. Due to the low numbers of basophils in blood, many experimental procedures are difficult to perform. Making researchers to rely on basophil cell lines or bone marrow derived basophils differentiated in vitro. Likewise, mast cells reach full maturation in tissues and mature mast cells are not found in the circulation1. Hence, researchers generally use established cell lines or mast cells differentiated in vitro from progenitor cells (i.e. cord blood, bone marrow). Accordingly, better understanding of mast cell and basophil development and maturation should yield better protocols for differentiating them in vitro. Currently, some contradictions arise from the literature regarding the cytokines and factors critical for mast cell and basophil differentiation. For example, while differentiation of murine bone marrow derived mast cells can be achieved with IL3 in the absence of stem cell factor (SCF), human mast cells are typically differentiated using IL6 and SCF. Manninka et al. have characterized in vitro culture conditions suitable for human mast cells and suggested that human mast cells arise from a committed progenitor distinct from other myeloid cells 3.
Since mast cells reach final maturation in tissues, it is plausible that other tissue‐resident cells supply additional maturation signals that may be responsible for the existing considerable heterogeneity.
Consistent with this notion, mast cells in various types of tissues present different phenotypes, such as connective tissue or mucosal mast cells. Hsieh et al.4 have shown that airway epithelial cells can provide necessary factors for expression of tryptase/chymase in cord blood differentiated mast cells. They also demonstrated that culture conditions affect their capacity to release leukotrienes. This finding is important since most studies tend to characterize human mast cells only by their protease content. Importantly, when attempting to study mast cells in vitro, one should consider the type of mast cell that is relevant for the physiological aspect of the study and adjust culture conditions, accordingly. Thus, to model human lung mast cells, special culture conditions may be required such as coculture with airway epithelial cells along with IL-3 and IL-4. 5
Cell differentiation is tightly regulated by transcription factors. Mast cell and basophil maturation and differentiation require GATA and STAT transcription factor families. 6,7However, new transcription factors continue to be discovered. In mice, interferon regulatory factor 8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates basophil and mast cell development 8. It is expressed in granulocyte progenitors but not in basophils, mast cells and basophil‐/mast cell‐restricted progenitors. However, in IRF8 knockouts, mast cell and basophil development is inhibited supporting a role in the generation of mast cell and basophil progenitors, likely involving its function as a transactivator of GATA2. 8 The complexity of the gene expression regulation during cell differentiation highlights the need for searching additional candidate transcription factors.
Current drugs used for mast cell and basophil induced pathologies are non-specific or target only a single mediator like antihistamines calling for more selective targets and knowledge about factors determining mast cell and basophil development. Improved in vitro systems to model the in vivo mast cell and basophil phenotypes are also crucial for the research community.
4
Mast Cell & Basophil Deficient Mouse StrainsThe role of mast cells was originally studied in mouse models carrying natural mutations in KIT, that is WBB6F-KIT W/W-v and C57BL6‐KIT W-sh/W-sh, which resulted in 99% depletion. However, due to altered KIT expression in other cell types, abnormalities of haematopoiesis and in the immune system have been described 9. Basophil in vivo research for long time was impossible lacking naturally occurring deficient mouse strains. First attempts were made using basophil‐depleting monoclonal antibodies: anti‐FcεRIα (clone Mar-1) or anti-CD200R3 (clone Ba103), an IgE‐independent activating receptor. Despite basophil depletion (>90%), reports of mast cell activation leading to anaphylaxis 10, depletion of dendritic cells 11 via FcεRI and activation of myeloid cells and natural killer cells through CD200R11,12 complicated the interpretation and needed further validation.
This triggered new mast cell and basophil depletion strategies, for example Cre recombinase models (usually under the control of mast cell or basophil associated proteases). Cre mediates constitutive depletion either by toxicity (Cpa3cre/Cre Master; Mcpt8-Cre) 10, 13 or by crossing with Rosa-DTα (R-DTA) mice expressing the diphtheria toxin (DT) α-subunit downstream a loxP-flanked stop cassette from the Rosa locus (Mcpt5-Cre-R-DTA, Basoph8). 14-16 Conditional depletion is achieved after injection of DT into DT receptor knock in mice, either by Cre inducible DTR (iDTR), in which DTR expression is blocked by an upstream loxP flanked stop sequence (Mcpt5‐Cre–iDTR)15,16 or by a mast cell/basophil protein‐ specific DTR transgenic mice (Mas‐TRECK, Bas‐TRECK, Mcpt8‐ DTR).17,18 A recent model, the red mast cell and basophil model (RMB), 19 allows tracking and depletion of both granulocytes selectively due to the insertion of the bright red tdTomato (tdT) fluorescent protein and the human DTR in the Ms4a2 gene encoding the FcεRI β-chain.
Mast cells and basophils are traditionally thought of in the context of TH2‐type responses; however, recent studies indicated roles beyond allergic and antihelminth responses (20, 21). Furthermore, significant differences in mast cell phenotypes derived from different mouse strains, different environment and different investigators have been identified influencing disease susceptibility.9 Hence, emphasis should
be made to carefully report experimental conduct, as well as detailed genetic backgrounds of mouse strains, animal husbandry and origin of mice.
The new deficient mouse models should allow to validate previous work performed with the KIT‐dependent mast cell deficiencies. Previous work in KIT W/W-v and KIT W-sh/W-sh mice showed that mast cells can contribute to orchestrating neutrophil recruitment in various inflammatory responses. IgE‐dependent local and systemic anaphylaxis reactions in both KIT‐dependent and independent mast cell‐deficient mice (KIT W/W-v mice, KIT W-sh/W-sh mice and mast cell-depleted Mcpt5-Cre–iDTR mice have consistently demonstrated a critical role of mast cells. 22-25 However, conflicting results regarding their role in contact hypersensitivity (CHS) responses have been generated. Researchers demonstrated that CHS responses to dinitrofluorobenzene (DNFB) were enhanced in KIT W/W-v and KIT W-sh/W-sh mice, while mast cells were critical for CHS responses to DNFB and fluorescein isothiocyanate when using Mcpt5-Cre–iDTR mice or Mcpt5-Cre–R-DTA mice. Additionally, immediate ear swelling response was abolished in Mcpt5‐Cre–iDTR mice but remained intact in the Kit‐mutant strains. Further studies are required to clarify the mechanisms that might explain these contradictory results. Similar validation and/or controversies applied also to other pathologies. Despite these discrepancies, previous studies on KIT-dependent and recent work on KIT-inKIT-dependent mast cell deficiencies should be seen as complementary.
Concerning basophils, generation of (inducible) basophildeficient mice allowed profound advances in the understanding of their immune regulatory and effector roles. Thus, basophil involvement in acquired tick feeding resistance demonstrated in the 1980s in guinea pigs 26 has been validated just recently, with the help of the Mcpt8-DTR mice.17, 18 However, conflicting results regarding the role of basophils in antigen presentation or TH2 response to papain have arisen in the literature when antibody‐mediated and genetically mediated basophil depletions have been compared .10, 27-30 Despite these controversies, basophil deficient mice represent new tools that allow deciphering the role of basophils in health and disease ranging as well as their regulatory role in humoral immune responses and autoimmune diseases. 31
4
Mast Cell & Basophil Deficient Mouse StrainsThe role of mast cells was originally studied in mouse models carrying natural mutations in KIT, that is WBB6F-KIT W/W-v and C57BL6‐KIT W-sh/W-sh, which resulted in 99% depletion. However, due to altered KIT expression in other cell types, abnormalities of haematopoiesis and in the immune system have been described 9. Basophil in vivo research for long time was impossible lacking naturally occurring deficient mouse strains. First attempts were made using basophil‐depleting monoclonal antibodies: anti‐FcεRIα (clone Mar-1) or anti-CD200R3 (clone Ba103), an IgE‐independent activating receptor. Despite basophil depletion (>90%), reports of mast cell activation leading to anaphylaxis 10, depletion of dendritic cells 11 via FcεRI and activation of myeloid cells and natural killer cells through CD200R11,12 complicated the interpretation and needed further validation.
This triggered new mast cell and basophil depletion strategies, for example Cre recombinase models (usually under the control of mast cell or basophil associated proteases). Cre mediates constitutive depletion either by toxicity (Cpa3cre/Cre Master; Mcpt8-Cre) 10, 13 or by crossing with Rosa-DTα (R-DTA) mice expressing the diphtheria toxin (DT) α-subunit downstream a loxP-flanked stop cassette from the Rosa locus (Mcpt5-Cre-R-DTA, Basoph8). 14-16 Conditional depletion is achieved after injection of DT into DT receptor knock in mice, either by Cre inducible DTR (iDTR), in which DTR expression is blocked by an upstream loxP flanked stop sequence (Mcpt5‐Cre–iDTR)15,16 or by a mast cell/basophil protein‐ specific DTR transgenic mice (Mas‐TRECK, Bas‐TRECK, Mcpt8‐ DTR).17,18 A recent model, the red mast cell and basophil model (RMB), 19 allows tracking and depletion of both granulocytes selectively due to the insertion of the bright red tdTomato (tdT) fluorescent protein and the human DTR in the Ms4a2 gene encoding the FcεRI β-chain.
Mast cells and basophils are traditionally thought of in the context of TH2‐type responses; however, recent studies indicated roles beyond allergic and antihelminth responses (20, 21). Furthermore, significant differences in mast cell phenotypes derived from different mouse strains, different environment and different investigators have been identified influencing disease susceptibility.9 Hence, emphasis should
be made to carefully report experimental conduct, as well as detailed genetic backgrounds of mouse strains, animal husbandry and origin of mice.
The new deficient mouse models should allow to validate previous work performed with the KIT‐dependent mast cell deficiencies. Previous work in KIT W/W-v and KIT W-sh/W-sh mice showed that mast cells can contribute to orchestrating neutrophil recruitment in various inflammatory responses. IgE‐dependent local and systemic anaphylaxis reactions in both KIT‐dependent and independent mast cell‐deficient mice (KIT W/W-v mice, KIT W-sh/W-sh mice and mast cell-depleted Mcpt5-Cre–iDTR mice have consistently demonstrated a critical role of mast cells. 22-25 However, conflicting results regarding their role in contact hypersensitivity (CHS) responses have been generated. Researchers demonstrated that CHS responses to dinitrofluorobenzene (DNFB) were enhanced in KIT W/W-v and KIT W-sh/W-sh mice, while mast cells were critical for CHS responses to DNFB and fluorescein isothiocyanate when using Mcpt5-Cre–iDTR mice or Mcpt5-Cre–R-DTA mice. Additionally, immediate ear swelling response was abolished in Mcpt5‐Cre–iDTR mice but remained intact in the Kit‐mutant strains. Further studies are required to clarify the mechanisms that might explain these contradictory results. Similar validation and/or controversies applied also to other pathologies. Despite these discrepancies, previous studies on KIT-dependent and recent work on KIT-inKIT-dependent mast cell deficiencies should be seen as complementary.
Concerning basophils, generation of (inducible) basophildeficient mice allowed profound advances in the understanding of their immune regulatory and effector roles. Thus, basophil involvement in acquired tick feeding resistance demonstrated in the 1980s in guinea pigs 26 has been validated just recently, with the help of the Mcpt8-DTR mice.17, 18 However, conflicting results regarding the role of basophils in antigen presentation or TH2 response to papain have arisen in the literature when antibody‐mediated and genetically mediated basophil depletions have been compared .10, 27-30 Despite these controversies, basophil deficient mice represent new tools that allow deciphering the role of basophils in health and disease ranging as well as their regulatory role in humoral immune responses and autoimmune diseases. 31
4
Taken together, while now ‘cleaner models’ for the study of mastcells and basophil functions have become available, the previous studies using KIT-dependent MC deficiencies and antibody mediated basophil depletion should still be considered as valid, despite the observed differences. One may want to keep in mind that the true mechanisms involving mast cells and basophils in pathologies may reside precisely in these differences.
Differences between human and mouse mast cells and basophils
Mouse mast cell and basophil models have been the mainstay of in vivo and in vitro investigations to study the causes and to identify cures for mast cell‐ and basophil‐driven diseases in humans. 32,33 Their use has provided valuable insight and triggered various hypotheses about mast cell and basophil-driven diseases and remains the prime tools for the identification of biological and pharmaceutical mast cell and basophil related targets.32,34 However, questions remain as to whether these models have been very useful in the identification of these targets for applications in humans. 23,35,36 Concise studies that examine the predictability of these models in human disease are still scanty. For example, recent large scale studies have shown that the small differences between the mouse and human genome can give rise to significant differences in their immune system and inflammatory response. 36, 37 It is therefore not surprising that several drugs for mast cell and basophil-related disease like asthma that were reported to be effective in preclinical models have failed in clinical trials. 38, 39 This warrants careful consideration in experimental design and the extrapolation of data to humans considering known differences between mouse and human mast cell and basophils. In this respect, some of the differences between mouse and human mast cells and basophils are summarized in Tables 1 and 2. These differences suggest that to enhance the chances of identifying clinically useful mast cell and basophil related targets, new models that precisely mimic human disease are needed. This will not only accelerate the identification of relevant targets, but will also result in efficient use of the already scarce resources available for research.
4
Taken together, while now ‘cleaner models’ for the study of mastcells and basophil functions have become available, the previous studies using KIT-dependent MC deficiencies and antibody mediated basophil depletion should still be considered as valid, despite the observed differences. One may want to keep in mind that the true mechanisms involving mast cells and basophils in pathologies may reside precisely in these differences.
Differences between human and mouse mast cells and basophils
Mouse mast cell and basophil models have been the mainstay of in vivo and in vitro investigations to study the causes and to identify cures for mast cell‐ and basophil‐driven diseases in humans. 32,33 Their use has provided valuable insight and triggered various hypotheses about mast cell and basophil-driven diseases and remains the prime tools for the identification of biological and pharmaceutical mast cell and basophil related targets.32,34 However, questions remain as to whether these models have been very useful in the identification of these targets for applications in humans. 23,35,36 Concise studies that examine the predictability of these models in human disease are still scanty. For example, recent large scale studies have shown that the small differences between the mouse and human genome can give rise to significant differences in their immune system and inflammatory response. 36, 37 It is therefore not surprising that several drugs for mast cell and basophil-related disease like asthma that were reported to be effective in preclinical models have failed in clinical trials. 38, 39 This warrants careful consideration in experimental design and the extrapolation of data to humans considering known differences between mouse and human mast cell and basophils. In this respect, some of the differences between mouse and human mast cells and basophils are summarized in Tables 1 and 2. These differences suggest that to enhance the chances of identifying clinically useful mast cell and basophil related targets, new models that precisely mimic human disease are needed. This will not only accelerate the identification of relevant targets, but will also result in efficient use of the already scarce resources available for research.
4
Mast cells and basophils as targets for tyrosine kinaseinhibitors
The non-redundant roles of mast cells and basophils in allergic disorders and systemic mastocytosis are well known. However, mast cells and basophils are increasingly recognized as important contributors to non-allergic inflammatory and autoimmune disorders. Several of the mast cell and basophil signalling pathways are regulated by tyrosine kinases (TKs). There are about 90 human TKs which regulate cell signalling and protein function by transferring a phosphate group from ATP to the hydroxyl group of a target protein tyrosine.42 About 90% of mastocytosis patients present the D816V mutation within the cytoplasmic tail of the receptor tyrosine kinase KIT. It results in constitutional KIT activation leading to the pathologic mast cell proliferation and mediator release.43, 44 TK signalling can be suppressed by tyrosine kinase inhibitors (TKIs) preventing phosphorylation of target proteins. As TKs are involved in mastocytosis, inhibitors have been considered as a feasible way for treatment. Furthermore, specific mast cells eradication may also be a means to treat mast cell-driven diseases.
Several TKIs that target mast cells and basophils are approved by the FDA for clinical use or are in the clinical trial phase. Imatinib was the first TKI used in mastocytosis patients; however, patients carrying the D816V mutation are resistant, as well as for nilotinib and ponatinib, which all target KIT. Subsequent trials focused on other compounds with a more broad inhibitory spectrum. Thus, dasatinib is inhibiting the SRC family protein TKs, whereas midostaurin also targets protein kinase C (PKC)45. Dasatinib and midostaurin, in addition to act on clonal mast cells and basophil diseases, have also been shown to be potent inhibitors of mast cell and basophil degranulation in vitro by targeting both the KIT and FcεRI receptor signalling pathways 46, 47. Nilotinib inhibits passive cutaneous anaphylaxis in mice and imatinib has shown effectiveness in ameliorating diarrhoea in a murine food allergy model.48, 49. Currently, a trial study is testing the effect of imatinib on treatment of resistant asthma (ClinicalTrials.gov identifier: NCT01097694). So far, all these studies have focused on the short-term effects of TKIs on KIT and IgE-mediated signalling. Results from long-term imatinib use in chronic myeloid leukaemia reveal that mast cell depletion can be achieved with less severe side effects compared to short-term
treatment, indicating that mast cell depletion can be another possible TKI therapeutic stratagem. 50
Since TKIs have a broad target profile and are not mast cell specific, they are associated with many adverse events depending on the particular TKI compound. These include periorbital oedema, nausea, cytopenia, folliculitis and pancreatitis, thereby limiting the usefulness in mild diseases.51 However, recent studies have shown the possibility of combining TKIs for synergistic effect. The big advantage is that patients can be treated by using lower drug concentrations, with possible fewer side effects but, fascinatingly, with much higher antineoplastic or even anti-allergic effect. As an example, the combination of ponatinib and midostaurin requires 75% less midostaurin and 66% less ponatinib in comparison with the individual use of the drugs to halve the proliferation speed (IC50) of HMC1.2 (KITD816V) cell lines. 52 Moreover, combinations with non-KIT-based therapies are currently being developed. For instance, synergistic apoptotic effect is observed after calcineurin phosphatase and KIT inhibition in KIT-mutant mast cell lines 53. Thus, TKIs can be used in multiple synergistic ways to still get a desired outcome in patients with the least systemic problems due to reduced side effects.
In conclusion, TKIs are potentially attractive compounds thus far reserved for severe treatment and resistant diseases. New developments with increasing specificity or the use of synergistic dosing schedules are promising to broaden the therapeutic spectrum, including less severe diseases. The benefit would be the low degree of side effects, which can be seen in the TKIs used in the clinic today.
4
Mast cells and basophils as targets for tyrosine kinaseinhibitors
The non-redundant roles of mast cells and basophils in allergic disorders and systemic mastocytosis are well known. However, mast cells and basophils are increasingly recognized as important contributors to non-allergic inflammatory and autoimmune disorders. Several of the mast cell and basophil signalling pathways are regulated by tyrosine kinases (TKs). There are about 90 human TKs which regulate cell signalling and protein function by transferring a phosphate group from ATP to the hydroxyl group of a target protein tyrosine.42 About 90% of mastocytosis patients present the D816V mutation within the cytoplasmic tail of the receptor tyrosine kinase KIT. It results in constitutional KIT activation leading to the pathologic mast cell proliferation and mediator release.43, 44 TK signalling can be suppressed by tyrosine kinase inhibitors (TKIs) preventing phosphorylation of target proteins. As TKs are involved in mastocytosis, inhibitors have been considered as a feasible way for treatment. Furthermore, specific mast cells eradication may also be a means to treat mast cell-driven diseases.
Several TKIs that target mast cells and basophils are approved by the FDA for clinical use or are in the clinical trial phase. Imatinib was the first TKI used in mastocytosis patients; however, patients carrying the D816V mutation are resistant, as well as for nilotinib and ponatinib, which all target KIT. Subsequent trials focused on other compounds with a more broad inhibitory spectrum. Thus, dasatinib is inhibiting the SRC family protein TKs, whereas midostaurin also targets protein kinase C (PKC)45. Dasatinib and midostaurin, in addition to act on clonal mast cells and basophil diseases, have also been shown to be potent inhibitors of mast cell and basophil degranulation in vitro by targeting both the KIT and FcεRI receptor signalling pathways 46, 47. Nilotinib inhibits passive cutaneous anaphylaxis in mice and imatinib has shown effectiveness in ameliorating diarrhoea in a murine food allergy model.48, 49. Currently, a trial study is testing the effect of imatinib on treatment of resistant asthma (ClinicalTrials.gov identifier: NCT01097694). So far, all these studies have focused on the short-term effects of TKIs on KIT and IgE-mediated signalling. Results from long-term imatinib use in chronic myeloid leukaemia reveal that mast cell depletion can be achieved with less severe side effects compared to short-term
treatment, indicating that mast cell depletion can be another possible TKI therapeutic stratagem. 50
Since TKIs have a broad target profile and are not mast cell specific, they are associated with many adverse events depending on the particular TKI compound. These include periorbital oedema, nausea, cytopenia, folliculitis and pancreatitis, thereby limiting the usefulness in mild diseases.51 However, recent studies have shown the possibility of combining TKIs for synergistic effect. The big advantage is that patients can be treated by using lower drug concentrations, with possible fewer side effects but, fascinatingly, with much higher antineoplastic or even anti-allergic effect. As an example, the combination of ponatinib and midostaurin requires 75% less midostaurin and 66% less ponatinib in comparison with the individual use of the drugs to halve the proliferation speed (IC50) of HMC1.2 (KITD816V) cell lines. 52 Moreover, combinations with non-KIT-based therapies are currently being developed. For instance, synergistic apoptotic effect is observed after calcineurin phosphatase and KIT inhibition in KIT-mutant mast cell lines 53. Thus, TKIs can be used in multiple synergistic ways to still get a desired outcome in patients with the least systemic problems due to reduced side effects.
In conclusion, TKIs are potentially attractive compounds thus far reserved for severe treatment and resistant diseases. New developments with increasing specificity or the use of synergistic dosing schedules are promising to broaden the therapeutic spectrum, including less severe diseases. The benefit would be the low degree of side effects, which can be seen in the TKIs used in the clinic today.
4
[60 ] Ta bl e 2: D iffer en ce b et w een h um an a nd m ou se b as ophi ls References1 Dahlin JS, Hallgren J. Mast cell progenitors: origin, development and migration
to tissues. Mol Immunol 2015;63:9–17.
2 Xiang Y, Eyers F, Young IG, Rosenberg HF, Foster PS, Yang M. Identification of
microRNAs regulating the developmental pathways of bone marrow derived mast cells. PLoS ONE 2014;9:e98139.
3 Maaninka K, Lappalainen J, Kovanen PT. Human mast cells arise from a common
circulating progenitor. J Allergy Clin Immunol 2013;132:463–9 e3.
4 Hsieh FH, Sharma P, Gibbons A, Goggans T, Erzurum SC, Haque SJ. Human
airway epithelial cell determinants of survival and functional phenotype for primary human mast cells. Proc Natl Acad Sci U S A. 2005;102:14380–5.
5 Oskeritzian CA, Zhao W, Pozez AL, Cohen NM, Grimes M, Schwartz LB.
Neutralizing endogenous IL-6 renders mast cells of the MCT type from lung, but not the MCTC type from skin and lung, susceptible to human recombinant IL-4-induced apoptosis. J Immunol 2004;172:593–600.
6 Ohmori S, Takai J, Ishijima Y et al. Regulation of GATA factor expression is
distinct between erythroid and mast cell lineages. Mol Cell Biol 2012;32:4742–55.
7 Verweij MM, Sabato V, Nullens S et al. STAT5 in human basophils: IL-3 is
required for its FcepsilonRI-mediated phosphorylation. Cytometry B Clin Cytom 2012;82:101–6.
8 Sasaki H, Kurotaki D, Osato N et al. Transcription factor IRF8 plays a critical role
in the development of murine basophils and mast cells. Blood 2015;125:358–69.
9 Galli SJ, Tsai M, Marichal T, Tchougounova E, Reber LL, Pejler G. Approaches for
analyzing the roles of mast cells and their proteases in vivo. Adv Immunol 2015;126:45–127.
10 Ohnmacht C, Schwartz C, Panzer M, Schiedewitz I, Naumann R, Voehringer D.
Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010;33:364–74.
11 Hammad H, Plantinga M, Deswarte K et al. Inflammatory dendritic cells–not
basophils–are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 2010;207:2097–111.
12 Kojima T, Obata K, Mukai K et al. Mast cells and basophils are selectively
activated in vitro and in vivo through CD200R3 in an IgEindependent manner. J Immunol 2007;179:7093–100.
13 Feyerabend TB, Weiser A, Tietz A et al. Cre-mediated cell ablation contests
mast cell contribution in models of antibody- and T cellmediated autoimmunity. Immunity 2011;35:832–44.
14 Dudeck A, Dudeck J, Scholten J et al. Mast cells are key promoters of contact
allergy that mediate the adjuvant effects of haptens. Immunity 2011;34:973–84.
15 Scholten J, Hartmann K, Gerbaulet A et al. Mast cell-specific Cre/loxP-mediated
4
[60 ] Ta bl e 2: D iffer en ce b et w een h um an a nd m ou se b as ophi ls References1 Dahlin JS, Hallgren J. Mast cell progenitors: origin, development and migration
to tissues. Mol Immunol 2015;63:9–17.
2 Xiang Y, Eyers F, Young IG, Rosenberg HF, Foster PS, Yang M. Identification of
microRNAs regulating the developmental pathways of bone marrow derived mast cells. PLoS ONE 2014;9:e98139.
3 Maaninka K, Lappalainen J, Kovanen PT. Human mast cells arise from a common
circulating progenitor. J Allergy Clin Immunol 2013;132:463–9 e3.
4 Hsieh FH, Sharma P, Gibbons A, Goggans T, Erzurum SC, Haque SJ. Human
airway epithelial cell determinants of survival and functional phenotype for primary human mast cells. Proc Natl Acad Sci U S A. 2005;102:14380–5.
5 Oskeritzian CA, Zhao W, Pozez AL, Cohen NM, Grimes M, Schwartz LB.
Neutralizing endogenous IL-6 renders mast cells of the MCT type from lung, but not the MCTC type from skin and lung, susceptible to human recombinant IL-4-induced apoptosis. J Immunol 2004;172:593–600.
6 Ohmori S, Takai J, Ishijima Y et al. Regulation of GATA factor expression is
distinct between erythroid and mast cell lineages. Mol Cell Biol 2012;32:4742–55.
7 Verweij MM, Sabato V, Nullens S et al. STAT5 in human basophils: IL-3 is
required for its FcepsilonRI-mediated phosphorylation. Cytometry B Clin Cytom 2012;82:101–6.
8 Sasaki H, Kurotaki D, Osato N et al. Transcription factor IRF8 plays a critical role
in the development of murine basophils and mast cells. Blood 2015;125:358–69.
9 Galli SJ, Tsai M, Marichal T, Tchougounova E, Reber LL, Pejler G. Approaches for
analyzing the roles of mast cells and their proteases in vivo. Adv Immunol 2015;126:45–127.
10 Ohnmacht C, Schwartz C, Panzer M, Schiedewitz I, Naumann R, Voehringer D.
Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010;33:364–74.
11 Hammad H, Plantinga M, Deswarte K et al. Inflammatory dendritic cells–not
basophils–are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J Exp Med 2010;207:2097–111.
12 Kojima T, Obata K, Mukai K et al. Mast cells and basophils are selectively
activated in vitro and in vivo through CD200R3 in an IgEindependent manner. J Immunol 2007;179:7093–100.
13 Feyerabend TB, Weiser A, Tietz A et al. Cre-mediated cell ablation contests
mast cell contribution in models of antibody- and T cellmediated autoimmunity. Immunity 2011;35:832–44.
14 Dudeck A, Dudeck J, Scholten J et al. Mast cells are key promoters of contact
allergy that mediate the adjuvant effects of haptens. Immunity 2011;34:973–84.
15 Scholten J, Hartmann K, Gerbaulet A et al. Mast cell-specific Cre/loxP-mediated
4
16 Sullivan BM, Liang HE, Bando JK et al. Genetic analysis of basophil function in
vivo. Natimmunol 2011;12:527–35.
17 Sawaguchi M, Tanaka S, Nakatani Y et al. Role of mast cells and basophils in IgE
responses and in allergic airway hyperresponsiveness. J Immunol 2012;188:1809–
18.Wada T, Ishiwata K, Koseki H et al. Selective ablation of basophils in mice
reveals their nonredundant role in acquired immunity against ticks. J Clin Invest. 2010;120:2867–75.
19 Dahdah A, Gautier G, Attout T et al. Mast cells aggravate sepsis by inhibiting
peritoneal macrophage phagocytosis. J Clin Invest 2014;124:4577–89.
20 Pellefigues C, Charles N. The deleterious role of basophils in systemic lupus
erythematosus. Curr Opin Immunol 2013;25:704–11.
21 Yu X, Kasprick A, Petersen F. Revisiting the role of mast cells in autoimmunity.
Autoimmun Rev 2015;14:751–9.
22 Arias K, Chu DK, Flader K et al. Distinct immune effector pathways contribute
to the full expression of peanut-induced anaphylacticreactions in mice. J Allergy Clin Immunol 2011;127:1552–61 e1.
23 Reber LL, Marichal T, Galli SJ. New models for analyzing mast cell functions in
vivo. Trends Immunol 2012;33:613–25.
24 Smith KA, Harcus Y, Garbi N, Hammerling GJ, MacDonald AS, Maizels RM. Type
2 innate immunity in helminth infection is induced redundantly and acts autonomously following CD11c(+) cell depletion. Infect Immun 2012;80:3481–9.
25 Sun J, Arias K, Alvarez D et al. Impact of CD40 ligand, B cells, and mast cells in
peanut-induced anaphylactic responses. J Immunol 2007;179:6696–703.
26 Brown SJ, Galli SJ, Gleich GJ, Askenase PW. Ablation of immunity to
Amblyomma americanum by anti-basophil serum: cooperation between basophils and eosinophils in expression of immunity to ectoparasites (ticks) in guinea pigs. J Immunol 1982;129:790–6.
27 Otsuka A, Nakajima S, Kubo M et al. Basophils are required for the induction of
Th2 immunity to haptens and peptide antigens. Nat Commun 2013;4:1739.
28 Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of
allergen-induced T helper type 2 responses. Nat Immunol 2008;9:310–8.
29 Tang H, Cao W, Kasturi SP et al. The T helper type 2 response to cysteine
proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 2010;11:608–17.
30 Yoshimoto T, Yasuda K, Tanaka H et al. Basophils contribute to T (H)2-IgE
responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat Immunol 2009;10:706–12.
31 Karasuyama H, Yamanishi Y. Basophils have emerged as a key player in
immunity. Curr Opin Immunol 2014;31:1–7.
32 Harvima IT, Levi-Schaffer F, Draber P et al. Molecular targets on mast cells and
basophils for novel therapies. J Allergy Clin Immunol 2014;134:530–44.
33 Reber LL, Frossard N. Targeting mast cells in inflammatory diseases. Pharmacol
Ther 2014;142:416–35.
34 LeiY,Gregory JA,NilssonGP,AdnerM. Insights intomast cell functions in asthma
using mouse models. Pulm Pharmacol Ther 2013;26:532–9.
35 Wall RJ, Shani M. Are animal models as good as we think? Theriogenology
2008;69:2–9.
36 Seok J, Warren HS, Cuenca AG et al. Genomic responses in mouse models
poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110:3507–12.
37 Mestas J, Hughes CC. Of mice and not men: differences between mouse and
human immunology. J Immunol 2004;172:2731–8.
38 Barnes PJ. New drugs for asthma. Semin Respir Crit Care Med 2012;33:685–94. 39 Holmes AM, Solari R, Holgate ST. Animal models of asthma: value, limitations
and opportunities for alternative approaches. Drug Discov Today 2011;16:659–70.
40 Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for
immune system investigation: progress, promise and challenges. Nat Rev Immunol 2012;12:786–98.
41 Kambe N, Hiramatsu H, Shimonaka M et al. Development of both human
connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body. Blood 2004;103:860–7.
42 Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human
genome. Oncogene 2000;19:5548–57.
43 Tobio A, Alfonso A, Botana LM. PKC potentiates tyrosine kinase inhibitors
STI571 and dasatinib cytotoxic effect. Anticancer Res 2014;34:3347–56.
44 Tobio A, Alfonso A, Botana LM. Cross-talks between c-Kit and PKC isoforms in
HMC-1(560) and HMC-1(560,816) cells. Different role of PKCdelta in each cellular line. Cell Immunol 2015;293:104–12.
45 Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of
systemic mastocytosis. Leuk Res 2011;35:1143–52.
46 Kneidinger M, Schmidt U, Rix U et al. The effects of dasatinib on IgE
receptor-dependent activation and histamine release in human basophils. Blood 2008;111:3097–107.
47 Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P.
Midostaurin (PKC412) inhibits immunoglobulin E dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy 2009;39:1711–20.
48 El-Agamy DS. Anti-allergic effects of nilotinib on mast cell-mediated
anaphylaxis like reactions. Eur J Pharmacol 2012;680:115–21.
49 Vaali K, Lappalainen J, Lin AH et al. Imatinib mesylate alleviates diarrhea in a
4
16 Sullivan BM, Liang HE, Bando JK et al. Genetic analysis of basophil function in
vivo. Natimmunol 2011;12:527–35.
17 Sawaguchi M, Tanaka S, Nakatani Y et al. Role of mast cells and basophils in IgE
responses and in allergic airway hyperresponsiveness. J Immunol 2012;188:1809–
18.Wada T, Ishiwata K, Koseki H et al. Selective ablation of basophils in mice
reveals their nonredundant role in acquired immunity against ticks. J Clin Invest. 2010;120:2867–75.
19 Dahdah A, Gautier G, Attout T et al. Mast cells aggravate sepsis by inhibiting
peritoneal macrophage phagocytosis. J Clin Invest 2014;124:4577–89.
20 Pellefigues C, Charles N. The deleterious role of basophils in systemic lupus
erythematosus. Curr Opin Immunol 2013;25:704–11.
21 Yu X, Kasprick A, Petersen F. Revisiting the role of mast cells in autoimmunity.
Autoimmun Rev 2015;14:751–9.
22 Arias K, Chu DK, Flader K et al. Distinct immune effector pathways contribute
to the full expression of peanut-induced anaphylacticreactions in mice. J Allergy Clin Immunol 2011;127:1552–61 e1.
23 Reber LL, Marichal T, Galli SJ. New models for analyzing mast cell functions in
vivo. Trends Immunol 2012;33:613–25.
24 Smith KA, Harcus Y, Garbi N, Hammerling GJ, MacDonald AS, Maizels RM. Type
2 innate immunity in helminth infection is induced redundantly and acts autonomously following CD11c(+) cell depletion. Infect Immun 2012;80:3481–9.
25 Sun J, Arias K, Alvarez D et al. Impact of CD40 ligand, B cells, and mast cells in
peanut-induced anaphylactic responses. J Immunol 2007;179:6696–703.
26 Brown SJ, Galli SJ, Gleich GJ, Askenase PW. Ablation of immunity to
Amblyomma americanum by anti-basophil serum: cooperation between basophils and eosinophils in expression of immunity to ectoparasites (ticks) in guinea pigs. J Immunol 1982;129:790–6.
27 Otsuka A, Nakajima S, Kubo M et al. Basophils are required for the induction of
Th2 immunity to haptens and peptide antigens. Nat Commun 2013;4:1739.
28 Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of
allergen-induced T helper type 2 responses. Nat Immunol 2008;9:310–8.
29 Tang H, Cao W, Kasturi SP et al. The T helper type 2 response to cysteine
proteases requires dendritic cell-basophil cooperation via ROS-mediated signaling. Nat Immunol 2010;11:608–17.
30 Yoshimoto T, Yasuda K, Tanaka H et al. Basophils contribute to T (H)2-IgE
responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat Immunol 2009;10:706–12.
31 Karasuyama H, Yamanishi Y. Basophils have emerged as a key player in
immunity. Curr Opin Immunol 2014;31:1–7.
32 Harvima IT, Levi-Schaffer F, Draber P et al. Molecular targets on mast cells and
basophils for novel therapies. J Allergy Clin Immunol 2014;134:530–44.
33 Reber LL, Frossard N. Targeting mast cells in inflammatory diseases. Pharmacol
Ther 2014;142:416–35.
34 LeiY,Gregory JA,NilssonGP,AdnerM. Insights intomast cell functions in asthma
using mouse models. Pulm Pharmacol Ther 2013;26:532–9.
35 Wall RJ, Shani M. Are animal models as good as we think? Theriogenology
2008;69:2–9.
36 Seok J, Warren HS, Cuenca AG et al. Genomic responses in mouse models
poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110:3507–12.
37 Mestas J, Hughes CC. Of mice and not men: differences between mouse and
human immunology. J Immunol 2004;172:2731–8.
38 Barnes PJ. New drugs for asthma. Semin Respir Crit Care Med 2012;33:685–94. 39 Holmes AM, Solari R, Holgate ST. Animal models of asthma: value, limitations
and opportunities for alternative approaches. Drug Discov Today 2011;16:659–70.
40 Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for
immune system investigation: progress, promise and challenges. Nat Rev Immunol 2012;12:786–98.
41 Kambe N, Hiramatsu H, Shimonaka M et al. Development of both human
connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body. Blood 2004;103:860–7.
42 Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human
genome. Oncogene 2000;19:5548–57.
43 Tobio A, Alfonso A, Botana LM. PKC potentiates tyrosine kinase inhibitors
STI571 and dasatinib cytotoxic effect. Anticancer Res 2014;34:3347–56.
44 Tobio A, Alfonso A, Botana LM. Cross-talks between c-Kit and PKC isoforms in
HMC-1(560) and HMC-1(560,816) cells. Different role of PKCdelta in each cellular line. Cell Immunol 2015;293:104–12.
45 Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of
systemic mastocytosis. Leuk Res 2011;35:1143–52.
46 Kneidinger M, Schmidt U, Rix U et al. The effects of dasatinib on IgE
receptor-dependent activation and histamine release in human basophils. Blood 2008;111:3097–107.
47 Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P.
Midostaurin (PKC412) inhibits immunoglobulin E dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy 2009;39:1711–20.
48 El-Agamy DS. Anti-allergic effects of nilotinib on mast cell-mediated
anaphylaxis like reactions. Eur J Pharmacol 2012;680:115–21.
49 Vaali K, Lappalainen J, Lin AH et al. Imatinib mesylate alleviates diarrhea in a
4
50 Cerny-Reiterer S, Rabenhorst A, Stefanzl G et al. Long-term treatment with
imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia. Oncotarget. 2015;6:3071–84.
51 Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review
on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470–81.
52 Gleixner KV, Peter B, Blatt K et al. Synergistic growth-inhibitory effects of
ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica 2013;98:1450–7.
53 Macleod AC, Klug LR, Patterson J et al. Combination therapy for KIT-mutant
mast cells: targeting constitutive NFAT and KIT activity. Mol Cancer Ther 2014;13:2840–51.
54 Moon TC, St Laurent CD, Morris KE et al. Advances in mast cell biology: new
understanding of heterogeneity and function. Mucosal Immunol 2010;3:111–28.
55 Gebhardt T, Sellge G, Lorentz A, Raab R, Manns MP, Bischoff SC. Cultured
human intestinal mast cells express functional IL-3 receptors and respond to IL-3 by enhancing growth and IgE receptor-dependent mediator release. Eur J Immunol 2002;32:2308–16.
56 Valent P, Besemer J, Sillaber C et al. Failure to detect IL-3-binding sites on
human mast cells. J Immunol 1990;145:3432–7.
57 Dahl C, Hoffmann HJ, Saito H, Schiotz PO. Human mast cells express receptors
for IL-3, IL-5 and GM-CSF; a partial map of receptors on human mast cells cultured in vitro. Allergy
2004;59:1087–96.
58 Jensen BM, Frandsen PM, Raaby EM, Schiotz PO, Skov PS, Poulsen LK.
Molecular and stimulus-response profiles illustrate heterogeneity between peripheral and cord blood-derived human mast cells. J Leukoc Biol 2014;95:893– 901.
59 Schernthaner GH, Hauswirth AW, Baghestanian M et al. Detection of
differentiation- and activation-linked cell surface antigens on cultured mast cell progenitors. Allergy 2005;60:1248–55.
60 Kraft S, Kinet JP. New developments in FcepsilonRI regulation, function and
inhibition. Nat Rev Immunol 2007;7:365–78.
61 Bischoff SC. Role of mast cells in allergic and non-allergic immune responses:
comparison of human and murine data. Nat Rev Immunol2007;7:93–104.
62 Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique
features. Front Immunol 2012;3:185.
63 Serra-Pages M, Olivera A, Torres R, Picado C, de Mora F, Rivera J. Eprostanoid 2
receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling. J Leukoc Biol 2012;92:1155–65.
64 Collington SJ, Westwick J, Williams TJ, Weller CL. The function of CCR3 on
mouse bone marrow-derived mast cells in vitro. Immunology 2010;129:115–24.
65 Juremalm M, Nilsson G. Chemokine receptor expression by mast cells. Chem
Immunol Allergy 2005;87:130–44.
66 Bradding P, Feather IH, Wilson S et al. Immunolocalization of cytokines in the
nasal mucosa of normal and perennial rhinitic subjects - the mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol 1993;151:3853–65.
67 van Beek AA, Knol EF, de Vos P, Smelt MJ, Savelkoul HF, van Neerven RJ.
Recent developments in basophil research: do basophils initiate and perpetuate type 2 T-helper cell responses? Int Arch Allergy Immunol 2013;160:7–17.
68 Mack M, Schneider MA, Moll C et al. Identification of antigencapturing cells as
basophils. J Immunol 2005;174:735–41.
69 Aljadi Z, Mansouri L, Nopp A et al. Activation of basophils is a new and sensitive
marker of biocompatibility in hemodialysis. Artif Organs 2014;38:945–53.
70 Reimer JM, Magnusson S, Juremalm M, Nilsson G, Hellman L, Wernersson S.
Isolation of transcriptionally active umbilical cord blood-derived basophils expressing Fc epsilon RI, HLA-DR and CD203c. Allergy 2006;61:1063–70.
71 Jonsson F, Daeron M. Mast cells and company. Front Immunol 2012;3:16. 72 Bakocevic N, Claser C, Yoshikawa S et al. CD41 is a reliable identification and
activation marker for murine basophils in the steady state and during helminth and malarial infections. Eur J Immunol 2014;44:1823–34.
73 Ebo DG, Bridts CH, Hagendorens MM, Aerts NE, De Clerck LS, Stevens WJ.
Basophil activation test by flow cytometry: present and future applications in allergology. Cytometry B Clin Cytom. 2008;74:201–10.
74 Torrero MN, Larson D, Hubner MP, Mitre E. CD200R Surface expression as a
marker of murine basophil activation. Clin Exp Allergy 2009;39:361–9.
75 Mukai K, Matsuoka K, Taya C et al. Basophils play a critical role in the
development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 2005;23:191–202.
76 Chirumbolo S. State-of-the-art review about basophil research in immunology
and allergy: is the time right to treat these cells with the respect they deserve? Blood transfusion = Trasfusione del sangue. 2012;10:148–64.
77 Eberlein B, Hann R, Eyerich S et al. Optimizing of the basophil activation test:
comparison of different basophil identification markers. Cytometry B Clin Cytom. 2015;88:183–9.
78 Shiratori I, Yamaguchi M, Suzukawa M et al. Down-regulation of basophil
function by human CD200 and human herpesvirus-8 CD200. J Immunol 2005;175:4441–9.
79 Sabato V, Verweij MM, Bridts CH et al. CD300a is expressed on human
basophils and seems to inhibit IgE/FcepsilonRI-dependent anaphylactic degranulation. Cytometry B Clin Cytom. 2012;82:132–8.
4
50 Cerny-Reiterer S, Rabenhorst A, Stefanzl G et al. Long-term treatment with
imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia. Oncotarget. 2015;6:3071–84.
51 Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review
on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470–81.
52 Gleixner KV, Peter B, Blatt K et al. Synergistic growth-inhibitory effects of
ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica 2013;98:1450–7.
53 Macleod AC, Klug LR, Patterson J et al. Combination therapy for KIT-mutant
mast cells: targeting constitutive NFAT and KIT activity. Mol Cancer Ther 2014;13:2840–51.
54 Moon TC, St Laurent CD, Morris KE et al. Advances in mast cell biology: new
understanding of heterogeneity and function. Mucosal Immunol 2010;3:111–28.
55 Gebhardt T, Sellge G, Lorentz A, Raab R, Manns MP, Bischoff SC. Cultured
human intestinal mast cells express functional IL-3 receptors and respond to IL-3 by enhancing growth and IgE receptor-dependent mediator release. Eur J Immunol 2002;32:2308–16.
56 Valent P, Besemer J, Sillaber C et al. Failure to detect IL-3-binding sites on
human mast cells. J Immunol 1990;145:3432–7.
57 Dahl C, Hoffmann HJ, Saito H, Schiotz PO. Human mast cells express receptors
for IL-3, IL-5 and GM-CSF; a partial map of receptors on human mast cells cultured in vitro. Allergy
2004;59:1087–96.
58 Jensen BM, Frandsen PM, Raaby EM, Schiotz PO, Skov PS, Poulsen LK.
Molecular and stimulus-response profiles illustrate heterogeneity between peripheral and cord blood-derived human mast cells. J Leukoc Biol 2014;95:893– 901.
59 Schernthaner GH, Hauswirth AW, Baghestanian M et al. Detection of
differentiation- and activation-linked cell surface antigens on cultured mast cell progenitors. Allergy 2005;60:1248–55.
60 Kraft S, Kinet JP. New developments in FcepsilonRI regulation, function and
inhibition. Nat Rev Immunol 2007;7:365–78.
61 Bischoff SC. Role of mast cells in allergic and non-allergic immune responses:
comparison of human and murine data. Nat Rev Immunol2007;7:93–104.
62 Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique
features. Front Immunol 2012;3:185.
63 Serra-Pages M, Olivera A, Torres R, Picado C, de Mora F, Rivera J. Eprostanoid 2
receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling. J Leukoc Biol 2012;92:1155–65.
64 Collington SJ, Westwick J, Williams TJ, Weller CL. The function of CCR3 on
mouse bone marrow-derived mast cells in vitro. Immunology 2010;129:115–24.
65 Juremalm M, Nilsson G. Chemokine receptor expression by mast cells. Chem
Immunol Allergy 2005;87:130–44.
66 Bradding P, Feather IH, Wilson S et al. Immunolocalization of cytokines in the
nasal mucosa of normal and perennial rhinitic subjects - the mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol 1993;151:3853–65.
67 van Beek AA, Knol EF, de Vos P, Smelt MJ, Savelkoul HF, van Neerven RJ.
Recent developments in basophil research: do basophils initiate and perpetuate type 2 T-helper cell responses? Int Arch Allergy Immunol 2013;160:7–17.
68 Mack M, Schneider MA, Moll C et al. Identification of antigencapturing cells as
basophils. J Immunol 2005;174:735–41.
69 Aljadi Z, Mansouri L, Nopp A et al. Activation of basophils is a new and sensitive
marker of biocompatibility in hemodialysis. Artif Organs 2014;38:945–53.
70 Reimer JM, Magnusson S, Juremalm M, Nilsson G, Hellman L, Wernersson S.
Isolation of transcriptionally active umbilical cord blood-derived basophils expressing Fc epsilon RI, HLA-DR and CD203c. Allergy 2006;61:1063–70.
71 Jonsson F, Daeron M. Mast cells and company. Front Immunol 2012;3:16. 72 Bakocevic N, Claser C, Yoshikawa S et al. CD41 is a reliable identification and
activation marker for murine basophils in the steady state and during helminth and malarial infections. Eur J Immunol 2014;44:1823–34.
73 Ebo DG, Bridts CH, Hagendorens MM, Aerts NE, De Clerck LS, Stevens WJ.
Basophil activation test by flow cytometry: present and future applications in allergology. Cytometry B Clin Cytom. 2008;74:201–10.
74 Torrero MN, Larson D, Hubner MP, Mitre E. CD200R Surface expression as a
marker of murine basophil activation. Clin Exp Allergy 2009;39:361–9.
75 Mukai K, Matsuoka K, Taya C et al. Basophils play a critical role in the
development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 2005;23:191–202.
76 Chirumbolo S. State-of-the-art review about basophil research in immunology
and allergy: is the time right to treat these cells with the respect they deserve? Blood transfusion = Trasfusione del sangue. 2012;10:148–64.
77 Eberlein B, Hann R, Eyerich S et al. Optimizing of the basophil activation test:
comparison of different basophil identification markers. Cytometry B Clin Cytom. 2015;88:183–9.
78 Shiratori I, Yamaguchi M, Suzukawa M et al. Down-regulation of basophil
function by human CD200 and human herpesvirus-8 CD200. J Immunol 2005;175:4441–9.
79 Sabato V, Verweij MM, Bridts CH et al. CD300a is expressed on human
basophils and seems to inhibit IgE/FcepsilonRI-dependent anaphylactic degranulation. Cytometry B Clin Cytom. 2012;82:132–8.
80 Phillips C, Coward WR, Pritchard DI, Hewitt CR. Basophils express a type 2
cytokine profile on exposure to proteases from helminths and house dust mites. J Leukoc Biol 2003;73:165–71.
81 Schroeder JT, Chichester KL, Bieneman AP. Human basophils secrete IL-3:
evidence of autocrine priming for phenotypic and functional responses in allergic disease. J Immunol 2009;182:2432–8.
82 Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. IL-33
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Chapter 5
Published in revised form: J Allergy Clin Immunol. 2018 Sep;142(3):1006-1008
